Learning drugs reawaken grown-up brain's inner child

WANNABE maestros, listen up. A mood-stabilising drug can help you achieve perfect pitch – the ability to identify any note you hear without inferring it from a reference note.

Since this is a skill that is usually acquired only early in life, the discovery is the first evidence that it may be possible to revert the human brain to a childlike state, enabling us to treat disorders and unlock skills that are difficult, if not impossible, to acquire beyond a certain age.

From bilingualism to sporting prowess, many abilities rely on neural circuits that are laid down by our early experiences. Until the age of 7 or so, the brain goes through several “critical periods” during which it can be radically changed by the environment. During these times, the brain is said to have increased plasticity.

In order to take advantage of these critical periods, the brain needs to be stimulated appropriately so it lays down the neuronal circuitry needed for a particular ability. For example, young children with poor sight in one eye may develop lazy eye, or amblyopia. It can be treated by covering the better eye, forcing the child to use the lazy eye – but this strategy only works during the critical period.

Advertisement

These windows of opportunity are fleeting, but now researchers are beginning to understand what closes them and how they might be reopened.

“We used to have this dogmatic view that the young brain is full of plasticity factors that disappear with age, and that’s why critical periods close,” says Takao Hensch, professor of neurology at Harvard University. “Then we realised that regardless of when the critical period is triggered, its length is finite. That suggested gene programs are unleashed that wind down plasticity.”

Hensch’s team has shown that several physiological changes close the door on plasticity in animals. A key player is histone deacetylase (HDAC), an enzyme that acts on DNA and makes it harder to switch genes on or off.

To test whether valproate might reawaken the critical period in humans, Hensch, together with Allan Young at King’s College London and colleagues, had to settle on a skill that appears impossible for adults to acquire. They chose perfect pitch because it is a rare ability and is usually seen only in some people who were taught music before the age of 6. There are no conclusive examples of adults acquiring it, although people who do months of training can gain some ability to identify notes.

The team gave 24 men with little or no musical training a dose of valproate or a placebo every day for 15 days. During the second week, participants watched a 10-minute training video daily, which taught them to associate six different tones over three octaves with six names, such as Sarah, David and Jimmy. The researchers used people’s names rather than the names of notes to ensure any existing familiarity with musical notation would not influence the results.

On the final day, the group heard 18 different tones and had to give the name associated with them. Men who took valproate identified 5.09 notes on average, a significantly better performance than those given the placebo, who got an average of 3.5 notes correct – no better than chance (Frontiers in Systems Neuroscience, doi.org/qq8).

The study is a promising first step towards demonstrating that critical-period learning can happen in adults, says Diana Deutsch, a psychologist at the University of California, San Diego. “The number of subjects explored here was small,” she says. “However the results were significant, and they should be taken very seriously.”

The team will now try to replicate the results in a bigger study, which will include an additional group taking a mood stabiliser that does not affect HDAC.

Studies looking at other drugs are already under way. One hinges on a second brake mechanism that could affect plasticity, involving genes that dampen the transmission of the nutrient choline around a cell. Donepezil, an Alzheimer’s drug, increases this transmission, so a team at Boston Children’s Hospital, which includes Hensch, is investigating whether it can help reverse amblyopia in older children and adults. The results are promising, says Hensch. “The first wave of subjects have improved. We don’t know how long it will last; we’re looking at that now.” Another study is focusing on the antidepressant fluoxetine, better known as Prozac.

Researchers are treading with caution, however. The brain shuts down critical periods for good reason – it would be disastrous to have it rewiring itself extensively for the rest of your life. Hensch says he would have been timid about testing valproate’s effects in humans except for the fact that it is an approved treatment for mood disorders and epilepsy. “We’re not opening the brain up to a massive rewrite. We’re enhancing its potential for plasticity – which, when paired with training, can manifest in changes we want.”

We’re not opening the brain up to a massive rewrite, we’re enhancing its potential for change

It’s difficult to predict the ramifications of this work, says Young, but they could be major. Several disorders, including autism, may be a result of mistimed critical periods (see “Timing is everything for blooming talents“) so switching them back on could be useful therapeutically. Then there is the potential to endow us with new skills. “If you can reopen that critical period, you could potentially reawaken learning in all,” says Young.

If you can reopen the brain’s critical period, you could reawaken learning in all of us

Timing is everything for blooming talents

Our developing brain is incredibly malleable, capable of structuring and restructuring connections between neurons in response to different experiences. Times of greatest change – or “sensitivity” – are called critical periods. These begin and end at certain ages (see graph) to allow the brain to build and cement circuitry for processes such as hearing, vision, emotion and language.

Sculpting these circuits involves a delicate balance of excitation and inhibition. Neurons that are excited, or active, at the same time will form robust connections, helping new circuits to form, while neurons that are inhibited or fire out of sync may become pruned.

Researchers have now shown that certain drugs might open up critical periods in adults (see main story). As well as potentially giving us a way to learn new skills, it may offer a path to tackle neurological disorders. For example, many genes implicated in autism are involved in establishing or maintaining the balance between excitation and inhibition. Some researchers believe the cognitive deficits seen in autism might be the result of mistimed critical periods. Studies of mice bred to express different autism-related genes have found evidence for such mistimings.

If critical periods don’t occur at the correct time, the brain may lay down some circuits too early, which means they may link up with underdeveloped brain areas. Or it can happen too late, in which case the functions these circuits handle, for example the ability to identify facial features, will not integrate with more sophisticated neural processes such as those that help us interpret others’ emotions.